The epidermal growth factor (EGF)-receptor and other similar growth factor receptor may play a central role in normal growth and development, and perhaps in the uncontrolled growth of tumors. The research proposed here deals with the sub-structure of the EGF-receptor protein, the structural basis of its several functional roles, and possible differences in these that might be important in development and in tumorigenesis. Our earlier studies on receptor processing in vivo and our more recent test tube studies on isolated receptor suggest that the receptor can be fragmented in a characteristic sequential fashion by a variety of proteolytic enzymes to yield well-defined products. Do these fragments carry distinct functional domains? This kind of question has been asked before, and answered affirmatively in IgG and in fibronectin. A similar demonstration for growth factor receptor would be of major significance. We propose to pursue this question in the EGF-receptor system. These experiments will utilize site specific monoclonal antibodies as a major tool. The same analytical tools will allow parallel experiments on receptor structure-function issues in cellular development and transformation. We have now been able to produce relatively large quantities of pure receptor, which makes it possible to consider a variety of important structure-function studies. Using these preparations, we plan to generate a collection of defined receptor fragments and site-specific monoclonal antibodies. These will be used to attack the following questions: 1) Are the sites responsible for EGF-binding activity, protein kinase activity, and membrane insertion immunologically distinguishable and/or proteolytically separable? 2) Do receptors from normal cells contain all the same antigenic determinants present in receptors from transformed cells? 3) Are there structural differences between EGF-rceptors from embryonic cells and adult or aged tissue?